ANTIARRHYTHMIC DRUGS

Introduction
Arrhythmias?
1. Extrasystoles (ES)
2. PSVT
3. Atrial Flutter (AFI)
4. Atrial Fibrillation(AF)
5. Ventricular tachycardia (VT)
6. Torsades de pointes
7. Ventricular fibrillation (VF)
8. AV Block

Classification of Antiarrhythmics

Class I Antiarrhythmics

The major mechanism of action of this group is Na+ channel

blockade limit the sodium conductance across the cell membrane.

SUBCLASS IA: open state Na+ channel blockers suppress AV

conduction & prolongs ERP.

Quinidine, Procainamide & Disopyramide belong to this group.

Quinidine is the oldest member. Seldom used.

Procainamide

Orally active amide derivative of procaine.

M/A: by blocking high frequency Na+ channels in the open state it

causes slowing of impulse conduction, prolongation of action potential
duration (APD), ERP, QT interval, QRS complex.

P/K: 75% oral bioavailability. Peak plasma concentrations reached in 1

hour. Metabolized in liver by acetylation & over half excreted
unchanged in urine. T1/2 3-4 hours.

A/E: nausea, vomiting.

CNS: weakness, confusion, hallucinations.

Flushing, hypotension on rapid IV injection.

Torsades de pointes, hypersensitivity reactions like rashes, fever,

angioedema. Aplastic anemia & agranulocytosis rarely occurs.

Over 50% on patients develop drug induced lupus on chronic high

doses especially the slow acetylators.

Use: IV procainamide effective in terminating monomorphic VT in 8090% cases.

Also used in medical Mx of WPW syndrome & to prevent recurrences of

VF.

Inconvenient for long term oral therapy due to multiple dosing & high
risk of lupus.

Dose: 0.5-1 g oral or IM for termination of arrhythmia f/b 0.25-0.5 g

every 2 hours or 500 mg IV loading dose f/b 2mg/kg/hour.

Disopyramide

It is quinidine like class IA drug with prominent cardiac depressant &

anticholinergic actions thus no effect on sinus rate because of two
opposing actions on heart rate.

Causes less marked PR interval prolongation & QRS broadening.

P/K: 80% oral bioavailability. Half metabolized in liver & half excreted
unchanged in urine. T1/2 6-8 hrs. in MI & renal failure.

A/E: better tolerated. Less GI S/E.

Anticholinergic effects like dry mouth, blurred vision, constipation,

urinary retention.

Cardiac decompensation & hypotension in patients with damaged

hearts.

C/I: sick sinus, BPH & heart failure.

Uses: second line drug for Px of ventricular arrhythmias. Maintenance

therapy after cardio- version of AF, AFI.

Class IB Antiarrhythmics

Lignocaine, Mexiletine

Blocks sodium channel in inactivated state.

Do not depress AV conduction or prolong APD, ERP & QT interval.

LIDOCAINE (LIGNOCAINE):

Most widely used local anesthetic drug.

Popular antiarrhythmic in ICU settings.

M/A: Blocks the Na+ channels in inactivated state. Normal tissues

minimally affected. Depolarized/damaged fibers significantly
depressed.

Causes suppression of automaticity in ectopic foci without affecting SA

node.

in APD & ERP of PF & ventricular muscles without affecting atrial

fibers.

No significant autonomic actions.

P/K: inactive orally due to high first pass metabolism. Undergoes rapid
redistribution. Thus action of an IV bolus dose lasts for 10-20 minutes
only. Propranolol prolongs the t1/2 by reducing hepatic blood flow.

Metabolized in liver (heaptic blood flow dependent) & excreted in

urine.

Dose: 50-100 mg IV bolus injection followed by 25-50 mg every 10-20

minutes.

A/E: dose related CNS effects like drowsiness, paresthesias, blurred

vision, disorientation, nystagmus, twitching & fits.

Least cardiotoxic & non proarrhythmic drug. Overdose can lead to

cardiac depression & hypotension.

Uses: ineffective in atrial arrhythmias.

Used only in ventricular arrhythmias.

Faster onset of action good drug in emergency settings like

arrhythmia following acute MI, during cardiac surgery etc.

Used for prevention & treatment of VF after an acute MI.

Also useful in digitalis induced arrhythmias.

MEXILETINE: Chemically & pharmacologically similar to lidocaine. But

active by oral route.

Complete oral absorption. 90% metabolized in liver & excreted in

urine. T1/2 9-12 hours.

S/E: bradycardia, aggravation of AV block, hypotension after IV

injection of Mexiletine.

Tremor, nausea, vomiting common. Dizziness, confusion, blurred vision

& ataxia can occur.

Use: as a lidocaine alternative for post MI arrhythmias. Used orally on

long term for suppression of VT.

Class IC Antiarrhythmics

Encainide, Flecainide, Propafenone

Most potent Na+ channel blockers. Highest action on open state Na+
channels. Longest recovery time.

Delay conduction, prolong PR, broaden QRS complex.

High proarrhythmic potential. Sudden deaths reported.

Propafenone

Markedly depress conduction. adrenergic blocker may precipitate

CHF or asthma.

Absorbed orally. Shows variable bioavailability & variable first pass

metabolism & variable t1/2 in different individuals.

S/E: nausea, vomiting, bitter taste, blurred vision & constipation.

Use: reserve drug for ventricular arrhythmia & to maintain sinus

rhythm in CHF.

Class II Antiarrhythmics ( Blockers)

Propranolol: cardiac receptor blockade antiarrhythmic action.

automaticity in SA node, PF & ectopic foci when it under adrenergic
influence.

Prolongs ERP of AV node slows down AV conduction. Thus prolongs

the PR interval.

Uses: useful in Rx of sinus tachycardia.

Also used in Rx of atrial & ventricular extrasystoles provoked by

emotions & exercise

Also used to control ventricular rate in AF/AFI

Highly effective in catecholamine induced arrhythmias as in

pheochromocytoma & halothane induced arrhythmias.

Also used for suppression of digitalis induced arrhythmias.

Used prophylactically after MI to reduce mortality due to arrhythmias.

Also used in WPW syndrome.

Sotalol: is also a class III antiarrhythmic blocks cardiac K+

channels prolongs repolarization.

Effective in polymorphic VT & for maintaining sinus rhythm in AF/AFI.

Dose dependent torsades de pointes is the major limitation to its use

contraindicated in patients with long QT interval.

Esmolol: quick & short acting (t1/2 10 mins.)

Given IV for emergency control of ventricular rate in AF/AFI.

Also used for controlling supraventricular & ventricular tachycardia.

Mainly used for termination of halothane induced arrhythmias.

Class III Antiarrhythmics

Amiodarone, bretylium

Blocks cardiac K+ channels prolonged repolarization; widening of AP

& prolongation of ERP.

Amiodarone: iodine containing, highly lipid soluble long acting

antiarrhythmic drug.

High & broad spectrum efficacy with low proarrhythmic potential

commonly used despite of its organ toxicity on long term.

M/A: myocardial K+ channel blockers prolongs APD & QT interval.

Blocks inactivated Na+ channel.

Inhibits myocardial K+ channels & bocks adrenoceptors.

Slows down the conduction & depress ectopic automaticity.

IV injection myocardial depression & BP.

P/K: incomplete & slow absorption from GIT.

Very slow onset of action develops over several days to weeks.

Acts rapidly on IV injection.

Cumulative accumulates in fat & muscles. Slowly released &

metabolized by CYP3A4 to active metabolite long duration of action.
T1/2 3-8 weeks.

Dose: 500 mg/day initially f/b 100 mg OD daily

Use: useful in wide range of supraventricular & ventricular

arrhythmias.

Mainly used for resistant VT & recurrent VF.

For maintenance of normal sinus rhythm in AF

Medical Mx of WPW syndrome

Long duration of action makes it suitable for long term prophylactic

therapy; has been found to reduce sudden cardiac death.

A/E: dose related. with duration of therapy.

Hypotension, bradycardia, cardiac depression occurs on IV injection &

on drug cumulation.

Nausea & GI upset on oral use in the loading phase.

Photosensitization & skin pigmentation in 10% patients. Reversible

corneal deposits common with long term use.

Most serious but rare toxicity on prolonged use is pulmonary alveolitis

& fibrosis. Can be prevented by daily doses < 200 mg/day.

Peripheral neuropathy & liver damage rare.

Interferes with thyroid function; goiter, hypo or hyperthyroidism may

occur on chronic use.

D/I: In patients receiving blockers or non DHP CCB, additive AV block

can occur.

Class IV Antiarrhythmics

Class IV drugs: verapamil & diltiazem (CCBs).

Verapamil: It depresses Ca++ mediated depolarization suppress

automaticity in SA node & PF & ectopic foci bradycardia.

Prolongs AV nodal ERP slowed conduction.

Uses & precautions:

PSVT: 5 mg IV can terminate an attack of PSVT in 80% cases.

60-120 mg TDS orally used to prevent recurrence.

Marked bradycardia, AV block, cardiac arrest or hypotension can

occur C/I in PSVT with CHF or hypotension.

To control ventricular rate in AF or AFI.

Poor efficacy in ventricular arrhythmias can not be used in post MI

prophylaxis.

C/I in partial heart block, sick sinus & VT.

In VT, it can precipitate VF in some patients.

Diltiazem: direct actions similar to verapamil but less prominent. Used as

an alternative to verapamil for PSVT.

Causes less in BP & myocardial depression can be used in

presence of CCF. Also can be easily titrated to target HR thus
preferred for ventricular rate control in AF or AFI.

Drugs for PSVT: Adenosine

More than 90% episodes of PSVT terminated within 30 seconds by

rapid IV injection of adenosine.

The A1 type of adenosine receptor is a GPCR present on SA node, AV

node & atrium.

It activates Ach sensitive K+ channels & causes membrane

hyperpolarization thus causing bradycardia, delayed conduction &
reduced excitability.

It has an ultrashort t1/2 10 seconds due to uptake into RBCs &

endothelial cells broken to inosine & 5 AMP.

Advantages of adenosine in PSVT are:

Equally efficacious or better than verapamil.

Action lasts <1 min transient S/E.

No hemodynamic deterioration can be given when verapamil is

contraindicated.

Can be given to patients with hypotension, CCF or those receiving

blockers.

Effective in patients not responding to verapamil.

A/E: transient dyspnoea, chest pain, fall in BP, flushing, ventricular

stand still or few seconds or VF. Bronchospasm in asthmatics. It has
brief action. Expensive. Cannot prevent recurrence.

Drugs for AV Block

Atropine: useful in AV block due to vagal overactivity e.g. digitalis

toxicity, post MI in dose of 0.6-1.2 mg IM.

Sympathomimetics (adrenaline, Isoprenaline):

Facilitates AV conduction & shortens ERP of conducting tissues may

overcome partial heart block.

Can also be used temporarily in complete heart block till external

pacemaker implanted.

Choice of Antiarrhythmics

Asymptomatic & minor arrhythmias e.g. most AES, occasional VES, first
degree AV block, bundle branch block in an otherwise normal heart, do
not require Rx.

Intensive therapy is indicated if:

If it is life threatening e.g. sustained VT, torsades de pointes.

Leads to hypotension, CCF & breathlessness.
Palpitation is marked e.g. PSVT, sustained VT, AF, torsades de pointes.
When a simple arrhythmia may lead to serious ones e.g. after MI

In all the above situations, drugs are needed for short periods. The
choice of antiarrhythmic depends on the following:

ECG diagnosis
Possible mechanism underlying arrhythmia.
Mechanism of action & range of activity of drug.
Pharmacokinetic profile of the drug.
Hemodynamic effects of the drug.

The aim is to improve cardiovascular function by restoring sinus

rhythm or by ventricular rate control.